tbuckley/cabot-search huggingface dataset:
Abstract 4068: Ganglioside SSEA4 in Ewing sarcoma: A marker of tumor cells with highly aggressive features and a potential immune target
Authors: Silke Jamitzky, Bianca Altvater, Carolin Krekeler, Laura Hoen, Caroline Brandes, Lisa Richter, Julia Ebbinghaus, Laurin Ochs, Nicole Farwick, Katja Urban, Dennis Görlich, Ian Johnston, Rita Pfeifer, Claudia Rossig, Wolfgang Hartmann, Sareetha Kailayangiri
Journal: Cancer Research (2023)

Abstract Cancers can aberrantly express carbohydrate antigens restricted to immature cells during prenatal human development, and these may be exploited for selective immune targeting. We studied expression and functional associations of the globo-series ganglioside stage-specific embryonic antigen 4 (SSEA4), a cell surface marker of human embryonic stem cells, in Ewing sarcoma (EwS). Flow cytometry revealed SSEA4 expression on the cell surface of each of 13 EwS cell lines, with moderate to high expression densities in 6 of 13 (46%) cell lines. Of 31 primary EwS tumor biopsies, 21 (68%) were SSEA4 positive by immunofluorescence staining. No associations of SSEA4 positivity with molecular or clinical disease parameters were found. Comparisons of paired tumor cell subpopulations with high and low/negative SSEA4 expression selected by cell sorting from 8 EwS cell lines revealed increased cell proliferation and colony formation of SSEA4high tumor cells, along with higher doxocrubicin chemoresistance and a higher propensity to migrate in transwell assays. SSEA4 negative cells selected from bulk populations of EwS cells regained SSEA4 expression during continued in vitro culture as well as after in vivo xenografting into immunodeficient mice. SSEA4high expression in EwS cells was not dependent on expression levels of the EWSR1-FLI1 fusion transcript or its direct targets, nor associated with markers of epithelial/mesenchymal plasticity. To retarget human T cells to SSEA4, we generated a second-generation, 41BBζ CAR using the antigen-binding domains of a murine anti-SSEA4 monoclonal antibody. SSEA4-specific CAR T cells specifically interacted with SSEA4 positive EwS cells in a strictly antigen-dependent manner, resulting in effective tumor cell lysis in vitro. We conclude that targeting of SSEA4 with CAR T cells or alternative immune therapeutics could be an attractive strategy to eliminate tumor cell subsets with high propensity to drive disease progression in EwS and therefore deserves further evaluation towards clinical translation. Citation Format: Silke Jamitzky, Bianca Altvater, Carolin Krekeler, Laura Hoen, Caroline Brandes, Lisa Richter, Julia Ebbinghaus, Laurin Ochs, Nicole Farwick, Katja Urban, Dennis Görlich, Ian Johnston, Rita Pfeifer, Claudia Rossig, Wolfgang Hartmann, Sareetha Kailayangiri. Ganglioside SSEA4 in Ewing sarcoma: A marker of tumor cells with highly aggressive features and a potential immune target. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4068.
Abstract 3956: Identifying PIKfyve as potential target in clear cell renal cell carcinoma with a loss of the von Hippel-Lindau tumor suppressor gene
Authors: Nadia Bouhamdani, Sandra Turcotte
Journal: Cancer Research (2023)

Abstract Background. Clear cell renal cell carcinoma (ccRCC) is the most frequent type of cancer in the kidney. These tumors are highly vascular and correlate with poor prognosis. Biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is a truncal event of ccRCC carcinogenesis, which yields new insights for targeted therapy. Our studies identified a small molecule, STF-62247, that is toxic to cells lacking VHL compared to RCC with a functional gene. We reported that STF-62247 blocks late stages of autophagy by targeting lysosome dynamics. Moreover, we identified lysosomal vulnerability in VHL-mutated ccRCCs, which could lead cells to death. Goal. This study aims to recognize and characterize STF-62247 potential targets. Results. Using biochemical approaches, our results indicated that STF-62247 cytotoxicity is driven by PIKfyve inhibition. Binding affinity between PIKfyve and STF-62247 is around 5 nM. Intracytoplasmic vacuoles and enlargement of endolysosomes were observed, which was prevented by adding exogenous PI(3,5)P2. Moreover, PIKfyve inhibitors such as apilimod, YM201636, Vacuolin-1, APY0201 sensitize ccRCC with a loss of VHL. Finally, genetic knockdown of PIKfyve was achieved by CRISPR/Cas9 leading VHL-inactivated cells to death. Conclusion. Altogether, our studies identified, for the first time, PIKfyve as potential target for kidney cancer cells with a loss of VHL. Citation Format: Nadia Bouhamdani, Sandra Turcotte. Identifying PIKfyve as potential target in clear cell renal cell carcinoma with a loss of the von Hippel-Lindau tumor suppressor gene. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3956.
Abstract 2169: NAD(P)H: quinone oxidoreductase 1 (NQO1)- A viable biomarker in colorectal cancer
Authors: Chaithanya Ganji, Bhaskar VK Lakkakula, Santosh Kumar Behera, Bassel F. El-Rayes
Journal: Cancer Research (2023)

Abstract Background/Objective: Colorectal cancer (CRC) is aggressive and widespread (3rd among malignancies) in the United States. NAD(P)H: Quinone Oxidoreductase 1 (NQO1) is an enzyme that contributes to chemoprotection for CRC. The aim of this meta-analysis is to test the connection between NQO1 C609T polymorphisms and CRC risk. Furthermore, the study explores the binding capacity and efficacy of BBI 608 against NQO1 in CRC through molecular docking. The inhibitor will then be tested in vitro. Methods: PubMed, Web of Science, and Google Scholar were used in bibliographic searches. For the NQO1 C609T analysis, a total of 18 studies were used. Data was gathered and subsequently calculated using the pooled odds ratio (OR) (95% confidence interval, CI). Molecular docking, Western Blot and QRT-PCR were used to determine the molecular function of BBI 608 and NQO1. Results: The relation between NQO1 polymorphism and CRC risk (TT + CT vs. CC: OR=1.19, 95% CI =1.06-1.34, p&amp;lt;0.001) was significant. Furthermore, stratified investigation based on ethnicity indicated significant association between NQO1 polymorphism and CRC risk (TT + CT vs. CC: OR=1.17, 95% CI =1.08-1.27, p&amp;lt;0.001). This study indicates that the C609T polymorphism of NQO1 is linked with CRC risk in Asians and Caucasians. To observe the molecular properties of BBI 608 (NQO1 inhibitor) and to analyze the exact mechanism of NQO1 on CRC, computational approaches were applied. This investigation provides a detailed understanding of the interaction between NQO1 and BBI 608 and its implication in CRC therapy. To support this computational analysis, in vitro studies were performed. BBI 608 creates higher cytotoxicity in a dose dependent manner in CRC cell lines. BBI 608 treatment significantly (p&amp;lt;0.001) reduced the NQO1 expression at protein and messenger levels in both CRC (HCT 116 and RKO) cell lines. Conclusion: Based on meta-analysis and computational approach, NQO1 is a viable biomarker and targeted molecule in CRC. In vitro results showed that inhibiting NQO1 with the drug BBI 608 decreased cell proliferation in both CRC cell lines. Knockout or overexpression or site directed mutagenesis is essential for a better understanding about BBI 608 targeted NQO1 and its amino acids. Citation Format: Chaithanya Ganji, Bhaskar VK Lakkakula, Santosh Kumar Behera, Bassel F. El-Rayes. NAD(P)H: quinone oxidoreductase 1 (NQO1)- A viable biomarker in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2169.
Abstract 347: Revealing the intracellular cytomatrix, immobilized biocatalysis, and concept of the operating cell
Authors: Tattym E. Shaiken
Journal: Cancer Research (2023)

Abstract The central problem of cell biology is the arrangement of biochemical reactions in the cytoplasm responsible for sustaining cellular life where, paradoxically, a myriad of metabolic reactions that could exclude each other coincide. Despite this well understood fact, the structural organization of the cytoplasm remains unclear, so far. Recent models indicate that cytoplasm contains viscous fluid and elastic solid phases. We separated the viscous fluid and elastic solid compartments, identifying them as the cytosol and cytomatrix, respectively. The distinctive composition of the cytomatrix included structural proteins, ribosomes, and metabolome enzymes. High-throughput analysis revealed unique biosynthetic pathways within the cytomatrix. The enrichment of biosynthetic pathways in the cytomatrix indicated the presence of immobilized biocatalysis. Enzymatic immobilization and segregation can surmount spatial impediments, and the local pathway segregation may form cytoplasmic organelles. Protein translation was reprogrammed within the cytomatrix under the restriction of protein synthesis by drug treatment. Thus, cytosol and cytomatrix are an elaborately interconnected network that promotes operational flexibility in healthy cells and the survival of malignant cells. Immobilized biocatalysis integrates the intracellular and extracellular matrices and receptors with the nuclear processes, thus removing the spatial hindrances for biochemical processes, which elucidates human cell operation. Citation Format: Tattym E. Shaiken. Revealing the intracellular cytomatrix, immobilized biocatalysis, and concept of the operating cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 347.
Abstract 3905: Epigenetic primming reveals the central role of epigenetic state in the anti-tumor activity of vitamin D in pancreatic ductal adenocarcinoma
Authors: Bo He, Lauren Stoffel, Clifford Jiajun He, Albert Mao Li, Haowen Jiang, Kumsun Cho, Brittany M. Flowers, Sofia Ferreira, Laura D. Attardi, Jiangbin Ye
Journal: Cancer Research (2023)

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, which is largely due to the intrinsic resistance to a broad spectrum of therapies. Vitamin D (VD) has been extensively studied as a potential preventive or therapeutic agent for PDAC treatment. Although accumulating evidence supports that VD has beneficial effects on PDAC treatment, controversies still exist. The major reason for this inconsistency is that VD resistance widely occurs in PDAC. However, the underlying mechanism by which the VD resistance occurs remains largely unknown. Here, we report that epigenetic primming by glyceryl triacetate (GTA) and 5-azacytidine (5-Aza) overcomes VD resistance in PDAC. Mechanistically, increasing global H3K27 acetylation with GTA and reducing global DNA methylation with 5-Aza not only elevate the VDR expression but also reprogram the VD responsive genes. Consistently, combination treatment with VD analogue calcipotriol (CPT) and epigenetic primming overcomes the VD resistance to inhibit cell proliferation and migration through activating genes involved in negative regulation of cell proliferation and cell migration, while CPT treatment alone has the opposite effects. Intriguingly, further studies in mouse PDAC cells suggest that VDR expression does not always corelate with VD responsiveness. Using the gain and loss of function experiments, we demonstrate that VDR is necessary but not sufficient to trigger the anti-tumor activity of VD, highlighting that epigenetic state is the key determinant of VD responsiveness in PDAC. Collectively, these data reveal a previously undefined mechanism for VD resistance in PDAC and has the potential to guide VD clinical trials in the future. Citation Format: Bo He, Lauren Stoffel, Clifford Jiajun He, Albert Mao Li, Haowen Jiang, Kumsun Cho, Brittany M. Flowers, Sofia Ferreira, Laura D. Attardi, Jiangbin Ye. Epigenetic primming reveals the central role of epigenetic state in the anti-tumor activity of vitamin D in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3905.
Abstract 946: A silver jubilee for synthetic lethality in cancer treatment: where do we stand
Authors: Joo Sang Lee, Youngmin Chung, Ashwin V. Kammula, Alejandro A. Schaffer, Eytan Ruppin
Journal: Cancer Research (2023)

Abstract Background: Synthetic lethality (SL) denotes a genetic interaction between two genes whose co-inactivation is detrimental to cells. Since the seminal paper of Hartwell and colleagues has raised the possibility that SL can be used to devise highly selective cancer treatments, it has been one of the promising approaches for precision oncology and drug discovery. Many different avenues have so far been explored to bring this idea to the clinic. As 25 years have passed by now, we take stock and systematically and comprehensively chart the landscape of SL-based preclinical research and clinical trials. Approach and Key Findings: We systematically mined both public and commercial databases to curate the preclinical and clinical landscape of the SL-based oncology studies. Our analysis shows that the number of SL oncology studies is rapidly growing since the first identification of the well-known BRCA-PARP synthetic lethality axis. Importantly, we find that the success rate of SL oncology trials is significantly higher than non-SL-based trials. While more than 70% of SL-oncology trials involve genes in the most-studied DNA damage response (DDR) pathways, the fraction of SL trials involving non-DDR pathways keeps growing since 2009. We further charted the landscape of SL triplets, which is a promising future higher-order extension of the conventional pairwise SL interactions. We find that only about 8% of preclinically validated SL triplets were clinically tested in trials, providing new opportunities for more refined clinical trial design. Our analysis suggests that emerging opportunities in SL oncology may arise from metabolic and paralogous interactions, disease-agnostic biomarkers, context-specific combinations against treatment resistance, artificial intelligence and data science approaches, and multi-omics patient stratification signatures. Significance: Taken together, our findings testify that a considerable potential benefits of SL based approaches are yet untapped, reinforcing the belief that the synthetic lethality approach may serve as a key driver of precision oncology going forward. Citation Format: Joo Sang Lee, Youngmin Chung, Ashwin V. Kammula, Alejandro A. Schaffer, Eytan Ruppin. A silver jubilee for synthetic lethality in cancer treatment: where do we stand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 946.
Abstract 4017: TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models
Authors: Jing Han, Mikhila Mahendra, Poojabahen Gandhi, Joseph R. Daniele, Caroline C. Carrillo, Benjamin J. Bivona, Ningping Feng, John V. Heymach, Funda Meric-Bernstam, Kei Oguchi, Shinji Mizuarai, Timothy P. Heffernan, Christopher P. Vellano, Joseph R. Marszalek
Journal: Cancer Research (2023)

Abstract Patients with brain tumors and metastases have poor prognosis and overall survival rates despite the advancements in neurosurgery, radiotherapy, and chemotherapy. Genomic alterations in HER2 are present in brain metastases of breast cancer (BC; ~20%) and non-small cell lung cancer (NSCLC; 13-20%), and EGFR alterations occur frequently in glioblastoma multiforme (GBM; &amp;gt;50%). Despite the advancements in standard of care options, optimal treatment management for these patients remains an unmet medical need. Recent evidence suggests activity of systemic therapy for immune and targeted therapies in the brain, including agents targeting HER2/EGFR. HER2-targeted tyrosine kinase inhibitors lapatinib, neratinib, and tucatinib and the HER2-targeted antibodies trastuzumab and pertuzumab, in combination with chemotherapy, have been shown to improve survival of patients with HER2 overexpressing BC in the presence of brain metastases. The limited penetration of these compounds into the CNS, however, limits their efficacy. TAS2940 is an irreversible pan-ErbB inhibitor with greater brain-penetrability than poziotinib, tucatinib, and neratinib. Here, we demonstrate that TAS2940 induces downregulation of phosphorylated HER2/EGFR, reduces tumor burden, and promotes a significant increase in survival in intracranial xenograft mouse models with HER2-amplification (BC), HER2-Exon20 insertion mutation (NSCLC), and EGFR-amplification (GBM). These promising preclinical data highlight potential novel therapeutic strategies for patients with EGFR-aberrant GBM and brain metastases harboring HER2/EGFR alterations, and may help support the advancement of the ongoing first-in-human clinical trial (NCT04982926) for TAS2940 in solid tumors with EGFR and/or HER2 alterations. Citation Format: Jing Han, Mikhila Mahendra, Poojabahen Gandhi, Joseph R. Daniele, Caroline C. Carrillo, Benjamin J. Bivona, Ningping Feng, John V. Heymach, Funda Meric-Bernstam, Kei Oguchi, Shinji Mizuarai, Timothy P. Heffernan, Christopher P. Vellano, Joseph R. Marszalek. TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4017.
Abstract 3738: A novel mechanism of STAT3 activation by genotoxic chemotherapy
Authors: Jaganathan Venkatesh, Magesh Muthu, Nuwan C. Acharige, Mary K. Pflum, Arun K. Rishi
Journal: Cancer Research (2023)

Abstract CARP-1, a perinuclear phospho-protein, is a biphasic regulator of cell survival and apoptosis signaling induced by genotoxic drugs. We have previously found that apoptosis induced by genotoxic drugs involved elevated levels of CARP-1. Exposure to genotoxic drugs also induced CARP-1 interaction with NF-κB kinase subunit γ (aka, NEMO) to promote NF-κB activation and cell survival. To further elucidate chemotherapy-activated, CARP-1-dependent cell survival mechanisms, we UV cross-linked protein extracts from Adriamycin-treated HeLa cervical cancer cells with a CARP-1 (614-638) peptide, and conducted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses of the peptide-bound protein complexes. This experiment revealed STAT3 interaction with CARP-1 (614-638) peptide. Our mutagenesis and co-IP-WB experiments revealed CARP-1 (550-650) directly interacts with a 40 amino acid peptide located in the STAT3 DNA binding domain. Overexpression of mutant STAT3 with in-frame-deletion of CARP-1/CCAR1-binding epitope (CE) peptide (Gst-STAT3 (ΔCE) mutant), but not Gst-STAT3 (WT), failed to translocate to nucleus in Adriamycin-treated cells. Disruption of STAT3-CARP-1 interaction or expression of STAT3 (ΔCE) mutant abolished Adriamycin-induced STAT3 Y705 and S727 phosphorylation. Collectively our data demonstrate that CARP-1 interaction with STAT3 regulates genotoxic chemotherapy-activated STAT3 and its nuclear translocation to promote cancer cell survival and growth. Citation Format: Jaganathan Venkatesh, Magesh Muthu, Nuwan C. Acharige, Mary K. Pflum, Arun K. Rishi. A novel mechanism of STAT3 activation by genotoxic chemotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3738.
Abstract 4492: A novel and potent FLT3 and IRAK4 dual inhibitor for the treatment of acute myeloid leukemia
Authors: Rui Yang, Lei Wu, Bing Zhang, Michael Xiang, Suyue Wang, Camille Xiang, Zhijian Lu, Jason Xiang
Journal: Cancer Research (2023)

Abstract Several potent FMS-like tyrosine kinase 3 (FLT3) inhibitors have been developed and approved for the treatment of FLT3-mutant acute myeloid leukemia (AML) recently. These inhibitors block the signaling pathways involved in proliferation of leukemic cells, and have shown favorable initial results in early-stage AML patients. However, a significant percentage of patients relapsed with poor prognoses. The relapse is generally caused by a compensatory innate immune stress response, such as Toll-like receptor activation, which induces adaptive resistance to the FLT3 inhibition. Interleukin-1 receptor associated kinase 4 (IRAK4) functions as a mediator of Toll-like receptor and interleukin-1 receptor signaling pathways. Patients harboring a U2AF1 or SF3B1 spliceosome mutation were found to express a longer and more active isoform of IRAK4 kinase, which could result in lasting activation of NF-κB and MAPK in oncogenic and innate immune signaling. Emavusertib (CA-4948), an IRAK4/FLT3 inhibitor, is currently in phase I clinical trials. To address the critically unmet medical needs of myeloid leukemia patients, we have developed a novel and potent FLT3 and IRAK4 dual inhibitor HPB-092 with excellent selectivity to provide durable efficacy in myeloid malignancies by eliminating adaptive resistance. HPB-092 significantly inhibited MV4-11 tumor cell proliferation at low nanomole concentration. HPB-092 demonstrated good oral bioavailability in several animal species. In a disseminated MV4-11 xenograft mouse model, HPB-092 displayed strong anti-tumor activity at 5mg/kg. HPB-092 was well-tolerated with no obvious adverse events at a dose of 40 mg/kg in two-weeks safety study in SD rats. In addition, no rhabdomyolysis side-effect was observed upon histological analysis. These results underscore the potential therapeutic benefit and safety profile of HPB-092 for the treatment of AML, especially in patients with mutations in U2AF1 or SFF3B1 spliceosome. Citation Format: Rui Yang, Lei Wu, Bing Zhang, Michael Xiang, Suyue Wang, Camille Xiang, Zhijian Lu, Jason Xiang. A novel and potent FLT3 and IRAK4 dual inhibitor for the treatment of acute myeloid leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4492.